EFFECT OF HALOPERIDOL AND CLOZAPINE ON THE DENSITY OF PERFORATED SYNAPSES IN CAUDATE, NUCLEUS-ACCUMBENS, AND MEDIAL PREFRONTAL CORTEX

Perforated synapses, which contain a discontinuous density along the postsynaptic membrane, can increase or decrease in numbers following various behavioral and biochemical manipulations. We have previously established that 14-day treatment with haloperidol causes an increase in the number of perforated synapses within the caudate nucleus (dorsolateral region) but not the nucleus accumbens (Meshul and Casey 1989). This effect was reversed if the animals were withdrawn from the drug for an equivalent period of time. We have now further examined the effects of haloperidol administration, which is associated with a high incidence of extrapyramidal side effects (EPS) and tardive dyskinesia (TD), and assessed the effects of clozapine, which appears to have a lower potential for inducing EPS and TD. Administration of haloperidol for 2 weeks significantly increased the percentage of perforated synapses in the caudate, but not in the nucleus accumbens or layer VI of medial prefrontal cortex (MPCx). There was an increase in specific [I-125]epidepride binding to D-2 receptors in the caudate nucleus and MPCx following haloperidol. Administration of clozapine for 2 weeks did not affect the percentage of perforated synapses in any of the three dopamine (DA)-rich regions that were examined. There was an increase in specific [H-3]SCH 23390 binding to D-1 receptors and in specific [I-125]epidepride binding to D-2 receptors only within MPCx following clozapine. The absence of any change in the density of perforated synapses within the dorsolateral caudate nucleus following clozapine correlates with: 1) the lack of effect on specific DA receptor binding or down regulation of serotonin (5-HT2) receptors (as reported by others), or 2) the inability in clozapine-treated animals to depolarize block substantia nigra (A9) DA neurons. These results may be related to the low incidence of EPS and TD observed with clozapine.